Role of alveolar nitric oxide in gastroesophageal reflux-associated cough: prospective observational study.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) measured at multiple exhalation flow rates can be used as a biomarker to differentiate central and peripheral airway inflammation. However, the role of alveolar nitric oxide (CaNO) indicating peripheral airway inflammation remains unclear in gastroesophageal reflux-associated cough (GERC). OBJECTIVES: We aimed to characterize the changes in alveolar nitric oxide (CaNO) and determine its clinical implication in GERC. DESIGN: This is a single-center prospective observational study. METHODS: FeNOs at exhalation flow rates of 50 and 200 ml/s were measured in 102 patients with GERC and 134 patients with other causes of chronic cough (non-GERC). CaNO was calculated based on a two-compartment model and the factors associated with CaNO were analyzed. The effect of anti-reflux therapy on CaNO was examined in 26 GERC patients with elevated CaNO. RESULTS: CaNO was significantly elevated in GERC compared with that in non-GERC (4.6 ± 4.4 ppb versus 2.8 ± 2.3 ppb, p < 0.001). GERC patients with high CaNO (>5 ppb) had more proximal reflux events (24 ± 15 versus 9 ± 9 episodes, p = 0.001) and a higher level of pepsin (984.8 ± 492.5 versus 634.5 ± 626.4 pg/ml, p = 0.002) in sputum supernatant than those with normal CaNO. More GERC patients with high CaNO required intensified anti-reflux therapy (χ2 = 3.963, p = 0.046), as predicted by a sensitivity of 41.7% and specificity of 83.3%. Cough relief paralleled a significant improvement in CaNO (8.3 ± 3.0 versus 4.8 ± 2.6 ppb, p < 0.001). CONCLUSION: Peripheral airway inflammation can be assessed by CaNO measurement in GERC. High CaNO indicates potential micro-aspiration and may predict a necessity for intensified anti-reflux therapy.

Role of CaNO in GERCWhy was the study done? This study aimed to investigate the role of concentration of alveolar nitric oxide (CaNO) as a biomarker for peripheral airway inflammation in patients with gastroesophageal reflux-associated cough (GERC). The evaluation of airway inflammation in GERC has not been widely practiced in clinical settings, and the potential of CaNO as a biomarker remained unclear.What did the researchers do? The researchers conducted a prospective study involving patients diagnosed with GERC and compared the changes in CaNO levels between GERC patients and those with cough due to other causes. The study also identified potential factors contributing to elevated CaNO levels in GERC patients relative to the normal range. Additionally, CaNO level changes were evaluated in a subgroup of GERC patients with initially elevated CaNO levels (n = 26).What did the researchers find? The study found that CaNO levels were significantly increased in GERC patients. Using a reference value for normal CaNO, the GERC patients were divided into a high CaNO cohort and a normal CaNO cohort. More proximal reflux episodes and higher level of pepsin in sputum supernatant were observed in the high CaNO cohort. Moreover, CaNO demonstrated moderate predictive value for the therapeutic efficacy of intensified anti-reflux therapy in GERC patients. After several weeks of anti-reflux therapy, CaNO levels significantly decreased along with the resolution of cough. These findings further confirmed the predictive value of CaNO for anti-reflux therapy.What do the findings mean? The findings suggest that CaNO may have the potential to be used as a non-invasive biomarker for detecting peripheral airway inflammation in GERC patients. Increased CaNO may be associated with potential micro-aspiration. Furthermore, high CaNO may predict the need for intensified anti-reflux therapy.

[Investigation of diagnostic methods and criteria for gastroesophageal reflux-related cough].

Gastroesophageal reflux-related cough is a multidisciplinary disease that cannot be diagnosed solely based on typical reflux-related symptoms. Its current diagnostic methods and criteria are largely derived from those used for gastroesophageal reflux disease, with slight differences. Esophageal reflux monitoring can provide objective evidence for the diagnosis of gastroesophageal reflux-related cough and is therefore the first-choice of laboratory tests recommended by the guidelines for cough management. Acid exposure time and syndrome association probability have been accepted as the diagnostic criteria, while esophageal motility assessment also has some certain auxiliary diagnostic value. Based on the existing evidence, we have reviewed how to improve the diagnostic methods and criteria for gastroesophageal reflux-related cough, as well as the issues that need to be addressed in the future.

[Esophageal dysmotility detection in patients with gastroesophageal reflux-related cough and its influence on the efficacy of anti-reflux therapy].

Objective: To investigate the characteristics of esophageal dysmotility in patients with an initial diagnosis of acid/non-acid gastroesophageal reflux-related cough (GERC), and its correlation with the therapeutic response to anti-reflux treatments to search for the useful indicators to screen patients with chronic cough suitable for anti-reflux therapy. Methods: A total of 173 patients with suspicious GERC who attended the Chronic Cough Specialist Clinic of Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University between June 2020 and December 2022 were retrospectively selected for the study. The age of the patients was (45.1±14.6) years old, including 87 males and 86 females. Their demographic characteristics, clinical manifestations, and the results of high-resolution manometry (HRM) and multichannel intraluminal impedance-pH monitoring (MII-pH) were collected. Information on the etiological identification process and final diagnosis was also recorded. The recruited cases were grouped according to therapeutic outcomes and divided into cases with a favourable response to conventional anti-reflux treatment, cases with a favourable response to intensified anti-reflux treatment, and cases with no response to anti-reflux treatment. Factors influencing the efficacy of anti-reflux treatment were investigated. Differences between groups were compared using the χ2 test, Student-Newman-Keuls test, and Kruskal-Wallis H(K) test, where applicable. Logistic regression analysis using forward stepwise regression based on maximum likelihood estimation was used to screen for influence factors. Results: The 175 patients with suspicious GERC included 45 (26.0%) patients who responded to conventional anti-reflux treatment, 54 (31.2%) who responded to intensified anti-reflux treatment and 74 (42.8%) who did not respond to anti-reflux therapies. Esophageal dysmotility was present in 52.0% of patients (90/173), but was less common in patients who responded to conventional anti-reflux treatment (χ2=8.09, P=0.018). Although the majority of reflux episodes were non-acid (136/173, 78.6%), the proportion of acid reflux (χ2=19.49, P<0.001) and acid exposure time (H=11.04, P=0.004) were significantly higher in patients who responded to conventional anti-reflux treatment. The patients with acid and non-acid GERC had comparable proportion of esophageal dysmotility (64.9% vs. 48.5%, χ2=3.11, P=0.078), with a shorter break [2.4 (0.7, 5.6) cm vs. 6.1 (1.4, 10.0) cm, Z=-2.39, P=0.017], longer upper esophageal sphincter [(4.1±0.9) cm vs. (3.7±1.3) cm, t=-2.09, P=0.038], higher percentage of normal esophageal contractions [60.0% (17.8%, 90.0%) vs. 30.0% (0, 80.0%), Z=-2.14, P=0.032], and lower percentage of large break [10.0% (0, 40.0%) vs. 50.0% (0, 100.0%), Z=-2.92, P=0.004] in the patients with non-acid GERC. The mean resting pressure of the lower esophageal sphincter was significantly lower (H=7.49, P=0.024), while the percentage of ineffective esophageal contractions was markedly higher (H=8.60, P=0.014) in the patients who responded to intensified anti-reflux treatment and in the patients who did not respond to the anti-reflux therapies. Multifactorial logistic regression analysis identified the percentage of ineffective contraction as an independent factor predicting the efficacy of conventional anti-reflux treatment, with a cut-off value of≤45% and a moderate predictive value (AUC=0.67, P=0.004). Conclusions: Esophageal dysmotility is common in GERC patients with different characteristics in acid and non-acid GERC. The percentage of ineffective esophageal contraction may be a useful indicator for selecting an anti-reflux strategy and predicting treatment outcomes.

Pathogenesis and management of gastroesophageal reflux disease-associated cough: a narrative review.

Background and Objective: Gastroesophageal reflux disease (GERD)-associated cough is defined as a special GERD with a predominant cough symptom and is a common cause of chronic cough. This review summarizes our current understanding on the pathogenesis and management of GERD-associated cough. Methods: Main literatures on the pathogenesis and management of GERD-associated cough were reviewed and our understandings derived from the published studies were showed then. Key Content and Findings: Although esophageal-tracheobronchial reflex mainly underlies the pathogenesis of GERD-associated cough, its counterpart-tracheobronchial-esophageal reflex might exist and initiate the cough due to reflux induced by upper respiratory tract infection through the signaling of transient receptor potential vanilloid 1 linking airway and esophagus. The presence of reflux-associated symptoms such as regurgitation and heartburn along with coughing suggests an association between cough and GERD, which is supported by the objective evidence of abnormal reflux as detected by reflux monitoring. Although there is no general consensus, esophageal reflux monitoring provides the main diagnostic criteria for GERD-associated cough. Despite that acid exposure time and symptom associated probability are useful and mostly employed reflux diagnostic criteria, they are imperfect and far from being the gold standard. Acid suppressive therapy has long been recommended as the first choice for GERD-associated cough. However, the overall benefits of proton pump inhibitors have been controversial and need to be further assessed, especially in patients with cough due to non-acid reflux. Neuromodulators have demonstrated potential therapeutic effects for refractory GERD-associated cough, for which anti-reflux surgery may also be a promising treatment option. Conclusions: Tracheobronchial-esophageal reflex might initiate reflux-induced cough provoked by the upper respiratory tract infection. It is necessary to optimize the current standards and to explore new criteria with higher diagnostic potency. Acid suppressive therapy is the first choice for GERD-associated cough, followed by neuromodulators and anti-reflux surgery for refractory GERD-associated cough.